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Mathematical Modeling of Reaction and Diffusion Systems in a Cell Including Surface Reactions on the Cytoplasmic Membranes
KTH, Skolan för datavetenskap och kommunikation (CSC), Numerisk analys, NA (stängd 2012-06-30).
KTH, Skolan för datavetenskap och kommunikation (CSC), Numerisk analys, NA (stängd 2012-06-30).ORCID-id: 0000-0003-4950-6646
2012 (Engelska)Rapport (Övrigt vetenskapligt)
Abstract [en]

Benzo[a]pyrene (BP) is a toxic polycyclic aromatic hydrocarbon (PAH) whichis found in our environment. These BPs are metabolized to benzo[a]pyrene diol(BPD) by enzymes bound to the cytoplasmic membranes e.g. members of thecytochrome P450 protein family and epoxide hydrolyses. BPDs are further metabolizedto two stereochemical variants of Benzo[a]pyrene diol expoxide (BPDE) bythe cytochrome P450 family of proteins. These are the two steps of metabolismcategorized as Phase I. In Phase II, BPDEs are further metabolized by soluble enzymesin the cytoplasm e.g. members of the glutathione transferase protein familyto GSH conjugates. BPDE can also diffuse into the cellular nucleus and reactwith DNA forming mutagenic DNA adducts. The formation of GSH conjugatesand DNA adducts, was earlier studied by us by developing a mathematical modeldescribing the intracellular reaction and diffusion of lipophilic PAHs taking intoaccount the partitioning phenomenon (Dreij K et al. PLoS One 6(8), 2011). In thispaper part of Phase I metabolism i.e formation of BPDE metabolites, will be addedto the model, thus enhancing the previous model. These cytochrome P450 reactionstake place on the intracellular membranes, and are modeled as a membranesurface reaction within the cytoplasm using the standard process of adsorption anddesorption. The effective equations are derived using iterative homogenization forthe numerical treatment of the cytoplasm including surface effects. The numericalresults of some of the species have been qualitatively verified against in vitroresults found in the literature.

Ort, förlag, år, upplaga, sidor
KTH Royal Institute of Technology, 2012. , s. 24
Serie
TRITA-NA ; 2012:4
Nationell ämneskategori
Beräkningsmatematik
Identifikatorer
URN: urn:nbn:se:kth:diva-93465OAI: oai:DiVA.org:kth-93465DiVA, id: diva2:516279
Forskningsfinansiär
Swedish e‐Science Research Center
Anmärkning

QC 20120418

Tillgänglig från: 2012-04-17 Skapad: 2012-04-17 Senast uppdaterad: 2014-01-29Bibliografiskt granskad
Ingår i avhandling
1. Computational Modeling of Reaction and Diffusion Processes in Mammalian Cell
Öppna denna publikation i ny flik eller fönster >>Computational Modeling of Reaction and Diffusion Processes in Mammalian Cell
2012 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

PAHs are the reactive toxic chemical compounds which are present as environmental pollutants. These reactive compounds not only diffuse through the membranes of the cell but also partition into the membranes. They react with the DNA of the cell giving rise to toxicity and may cause cancer. To understand the cellular behavior of these foreign compounds, a mathematical model including the reaction-diffusion system and partitioning phenomenon has been developed. In order to reduce the complex structure of the cytoplasm due to the presence of many thin membranes, and to make the model less computationally expensive and numerically treatable, homogenization techniques have been used. The resulting complex system of PDEs generated from the model is implemented in Comsol Multiphysics. The numerical results obtained from the model show a nice agreement with the in vitro cell experimental results. Then the model was reduced to a system of ODEs, a compartment model (CM). The quantitative analysis of the results of the CM shows that it cannot fully capture the features of metabolic system considered in general. Thus the PDE model affords a more realistic representation. In order to see the influence of cell geometry in drug diffusion, the non-spherical axi-symmetric cell geometry is considered, where we showed that the cellular geometry plays an important role in diffusion through the membranes. For further reduction of complexity of the model, another simplified model was developed. In the simplified model, we used PDEs for the extracellular domain, cytoplasm and nucleus, whereas the plasma and nuclear membranes were taken away, and replaced by the membrane flux, using Fick's Law. We further extended the framework of our previously developed model by benchmarking against the results from four different cell lines. Global optimization techniques are used for the parameters describing the diffusion and reaction to fit the measured data. Numerical results were in good agreement with the in vitro results. For the further development of the model, the process of surface bound reactions were added, thus developing a new cell model. The effective equations were derived using iterative homogenization for this model. The numerical results of some of the species were qualitatively verified against the in vitro results found in literature.

Ort, förlag, år, upplaga, sidor
Stockholm: KTH Royal Institute of Technology, 2012. s. xiii, 52
Serie
Trita-CSC-A, ISSN 1653-5723 ; 2012:03
Nationell ämneskategori
Beräkningsmatematik
Identifikatorer
urn:nbn:se:kth:diva-93466 (URN)978-91-7501-315-2 (ISBN)
Disputation
2012-05-15, E2, Lindstedsvägen 3, KTH, Stockholm, 10:00 (Engelska)
Opponent
Handledare
Anmärkning
QC 20120419Tillgänglig från: 2012-04-19 Skapad: 2012-04-17 Senast uppdaterad: 2012-04-19Bibliografiskt granskad

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Hanke, Michael

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Chaudhry, Qasim AliHanke, Michael
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Numerisk analys, NA (stängd 2012-06-30)
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